The use of taxanes, such as paclitaxel, as anti-tumor agents for patients suffering from diseases such as ovarian and breast cancer, is known. In addition, paclitaxel has been shown to be clinically potent as a synergistic agent when used in conjunction with radiation treatment. Paclitaxel has a unique mechanism of action and a broad spectrum of anticancer activity because paclitaxel shows stabilization of microtubules rather than disassembly of microtubules.
However, paclitaxel has extremely low solubility in water, which makes it difficult to provide a suitable dosage form. Currently, paclitaxel is prepared and administered in a vehicle containing Cremophor EL (a polyethoxylated castor oil) and ethanol in a 50:50 (vol/vol) ratio. This solution is diluted 1:10 in saline before being administered to humans. The stability of paclitaxel once diluted in saline solution is quite low. The drug degrades within 24 hours and, thus, handling of dosage for the patients becomes very difficult. Since, the drug precipitates from dilution, an on-line filter is utilized for the infusion of the drug to the patients.
In clinical trials, a consistent problem of anaphylactoid reaction, dyspnea, hypertension, and flushing have been encountered. The dose-limiting toxicity is myelosuppression which necessitates patient hospitalization when the drug is used.
Attempts to prevent paclitaxel cardiotoxicity and anaphylactoid reaction have included reliance on pretreatment of patients with antihistamine and corticosteroids, and by prolonging the infusion time from six to twenty four hours. U.S. Pat. No. 5,621,001 (Canetta et al.) discloses a prolonged infusion time in a method for reducing peripheral neurotoxicity symptoms while maintaining an anti-tumor effect in patients suffering from ovarian cancer and undergoing paclitaxel therapy. This method involves administering about 135 mg/m2 of paclitaxel over a period of about 24 hours. The administration of paclitaxel is repeated at least once, about 21 days after the preceding administration.
U.S. Pat. No. 5,665,761 (Canetta et al.) discloses a pretreatment stage before administration of paclitaxel. The '761 patent provides for paclitaxel infusions over a duration of less than six hours, preferably about three hours, utilizing dosages of between about 135 mg/m2 and about 275 mg/m2, preferably between about 135 mg/m2 and about 175 mg/m2, after patients had been pretreated to alleviate or minimize hypersensitivity responses. For example, the patients are pre-medicated with steroids, antihistamines, and H2-antagonists sufficient to at least prevent an anaphylactoid shock capable of causing acute hypersensitivity reactions and patient death. U.S. Pat. No. 5,670,537 (Canetta et al.) also discloses this method of administration for a patient suffering from a paclitaxel-sensitive tumor, such as an ovarian tumor.
U.S. Pat. No. 5,641,803, discloses the administration of paclitaxel to a patient, wherein about 135-175 mg/m2 of paclitaxel is administered over a period of about three hours. Such a period purportedly was used to overcome, in part, some of the aforementioned problems associated with short infusion times, such as one hour, which had been employed with the conventional paclitaxel formulations containing polyethoxylated castor oil.
In yet another attempt to address the toxicity concerns of the conventional paclitaxel formulation, U.S. Pat. No. 5,696,153 suggests the use of an administration regimen wherein 45 to 120 mg/m2 of paclitaxel is administered over a period of 60 to 180 minutes, a plurality of times during a 21 day period, with each infusion being separated by an interval of between 4 to 5 days.
However, even with these manipulations of prolonged infusion time and pretreatment of patients with antihistamines and corticosteroids, the patients suffer from serious toxicities which are often fatal. Different agent delivery systems are being utilized to enhance tumor cell-fighting effects of the drug and/or reduce systemic toxicity. Liposomes are one of many carriers that have been developed to help anti-tumor agents become more efficient and less toxic. A “liposome” is a closed structure composed of lipid bi-layers surrounding an internal aqueous space.
U.S. Pat. No. 5,648,090 (Rahman et al.) and U.S. Pat. No. 5,424,073 (Rahman et al.) provide a liposomal encapsulated paclitaxel for a method for treating cancer in mammals using such a liposomal-encapsulated paclitaxel, or antineoplastic derivative thereof. The '090 and '073 patents disclose a method of modulating multidrug resistance in cancer cells in a mammalian host by administering to the host a pharmaceutical composition of a therapeutically effective number of liposomes which include a liposome-forming material, cardiolipin, and an agent such as paclitaxel, or an antineoplastic derivative of paclitaxel, or a mixture thereof; and a pharmaceutically acceptable excipient.
Up until the present invention the fastest administration time tolerated by most patients was optimally a three hour time period. Consequently, there is a need for methods for rapidly administering high concentrations of taxane in human cancer patients without inducing a toxic reaction. Such methods would improve the efficacy of taxane therapy and alleviate the discomfort and toxicity associated with previously known taxane administration methods. The present invention provides such a method.